The present invention provides an assay which will increase the therapeutic value of stroke treatment by identifying patients who can benefit from such treatment in a more reliable and timely manner, which is expected to greatly increase the number of patients considered eligible for this treatment by at least five-fold.
PCT application PCT/JP2010/062631, published as WO2011/013668 and filed as a continuation-in-part in the United States as U.S. Ser. No. 13/359,281, now U.S. Pat. No. 8,652,476 describes methods to treat cerebral infarction or ischemia in humans by administering a combination of a thrombolytic intervention and an inhibitor of VEGF-receptor mediated signal transduction during the acute stage of the cerebral ischemic event which is considered to be within 6 hours after the onset of the cerebral infarction, with the combination providing reduced toxicity as compared to thrombolytic intervention alone. Determining the time of the onset of cerebral infarction, however, is difficult as typically the subject is not under medical supervision at that time. In addition, for cerebral infarction specifically, the treatment window appears to be critical. Presence of a disrupted BBB in a subject with embolic stroke is a risk factor for hemorrhage after thrombolysis. It is thus reasonable in hindsight that the levels of a blood-brain barrier disruption promoting factor, such as VEGF, correlates inversely with thrombolytic safety.
A variety of thrombolytic inventions is described in the literature as is a variety of methods to inhibit VEGF-receptor mediated signal transduction. For example, the thrombolytic invention may include a plasminogen activator such as tissue plasminogen activator (tPA), urokinase, streptokinase or their analogs, other plasminogen activators such as that derived from vampire bats, or mechanical destruction or removal of the embolus. The inhibitor of VEGF-receptor mediated signal transduction may be a specific binding partner for VEGF or VEGF-R or a compound that inhibits the release of VEGF from platelets or a compound that disrupts signal transduction from activated VEGF-R.
The above documents, and all others cited herein are incorporated by reference.
Thrombolytics like tPA are currently used in only a few percent of stroke patients due to the toxicity risk, which is exacerbated when given more than 3 hours after the stroke. With adjunct therapy available to reduce the toxicity of tPA, the patient population expected to benefit from such treatment is considerably increased. This combination of interventions, however, according to the PCT document depends on clock time from a starting point that is notoriously difficult to determine. It would be useful to have instead a method to determine the suitable treatment window that relies on physiological status.
Moreover, the severity of the stroke is proportional to the degree of disruption of the blood brain barrier (BBB). The most severe strokes also benefit the most from thrombolytic therapy. In light of the risk of toxicity from plasminogen activators, therefore, their use is currently avoided for mild strokes, even though full clot dissolution is easier to achieve in such cases. Thus, measuring degree of disruption of the BBB provides a combined measure of stroke timing and severity, and it is considered that more severe strokes warrant the risks associated with this treatment. Currently, this assessment is made following a CT scan at the hospital, resulting in substantial delay in treatment compared to the optimal early administration of thrombolytic agents. A measure suitable for assessing BBB disruption by a point of care assay feasible to use in the ambulance is provided by the present invention. In pilot studies using an ambulance equipped with a portable CT scanner to reduce the delay in diagnosis, substantial reduction in the time required to select thrombolytic intervention was achieved over standard of care; Walter, S., Lancet Neurology (2012) 11:397-404. However, the high cost of a portable CT scanner makes it important to develop a simpler point of care diagnostic for stroke severity.